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Autoimmune hepatitis with acute presentation in Japan
Digestive and Liver Disease 42 (2010) 51–54
Contents lists available at ScienceDirect
Digestive and Liver Disease journal homepage: www.elsevier.com/locate/dld
Liver, Pancreas and Biliary Tract
Autoimmune hepatitis with acute presentation in Japan Y. Miyake a,b,∗ , Y. Iwasaki b , H. Kobashi b , T. Yasunaka b , F. Ikeda a,b , A. Takaki b , K. Yamamoto a,b a b
Department of Molecular Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan Department of Gastroenterology & Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
a r t i c l e
i n f o
Article history: Received 21 November 2008 Accepted 15 April 2009 Available online 26 May 2009 Keywords: Acute exacerbation Acute hepatitis Cirrhosis Zone 3 necrosis
a b s t r a c t Background: In Caucasians with autoimmune hepatitis, patients with acute presentation have autoimmune thyroiditis and histological zone 3 necrosis more frequently. Aim: We aimed at investigating clinical features of Japanese autoimmune hepatitis patients with acute presentation. Methods: Of 176 patients retrospectively reviewed, 53 were diagnosed with acute presentation. Results: Patients with acute presentation had higher serum levels of bilirubin and transaminase, lower frequencies of autoimmune thyroiditis and antinuclear antibodies of 1:160 or greater, and a higher frequency of zone 3 necrosis. Of the 53 patients with acute presentation, 10 showed histological acute hepatitis; however, advanced staging of fibrosis was found in 13 patients. In patients with acute presentation, those with histological acute hepatitis were younger than those with chronic hepatitis. The cumulative incidental rate of the normalization of serum alanine aminotransferase levels with prednisolone treatment was similar between patients with acute presentation and those with classical presentation. Conclusions: In line with previous results, zone 3 necrosis is a histological characteristic of autoimmune hepatitis with acute presentation. Autoimmune hepatitis with acute presentation includes not only histological acute hepatitis but also acute exacerbation of pre-existing chronic disease. On the other hand, Japanese patients with acute presentation may also have different clinical features from Caucasian patients. © 2009 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.
1. Introduction Autoimmune hepatitis (AIH), defined as a chronic hepatitis of unknown aetiology, is characterized by circulating autoantibodies, hypergammaglobulinemia, and the presence of interface hepatitis and lymphoplasmacytic infiltration on histological examination [1,2]. The prognosis is generally good with immunosuppressive treatment. Recently, the number of patients with acute presentation has increased. Czaja and co-workers [3] reported that acute and classical presentation of AIH were indistinguishable from each other by clinical and laboratory features. In contrast, Hofer et al. [4] reported that zone 3 necrosis was a histological characteristic of AIH with acute presentation. Kessler et al. [5] reported that patients with acute presentation had severe hepatitis and autoimmune thyroiditis more frequently than those with classical presentation. The clinical features of AIH with acute presentation have not been fully elucidated.
∗ Corresponding author at: Department of Molecular Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1, Shikata-cho, Okayama 700-8558, Japan. Tel.: +81 86 235 7219; fax: +81 86 225 5991. E-mail address: [email protected] (Y. Miyake).
On the other hand, the clinical features of Japanese AIH patients are different from those of Caucasian patients [2]. These are attributed to differences in human leukocyte antigen (HLA) DR status. In Caucasian patients, HLA DR3 and DR4 are independently susceptible to AIH [6], while DR4 is predominant in Japanese patients; there are few Japanese patients with DR3 [7]. Patients with DR3 are younger and have a higher frequency of treatment failure; however, those with DR4 frequently have concurrent extrahepatic autoimmune disease and respond better to corticosteroid treatment [8]. The clinical features of AIH with acute presentation may differ between Japanese and Caucasian patients. In the present study, we assessed the clinical features of Japanese AIH patients with acute presentation. 2. Patients and methods One-hundred-and-seventy-six patients with type 1 AIH (153 females, 23 males, median age 55 years) were admitted to the Okayama University Hospital or six affiliated hospitals between March 1989 and April 2008. All patients were seronegative for hepatitis B surface antigen, anti-hepatitis C virus antibody, hepatitis C virus RNA, and anti-mitochondrial antibody, and all underwent liver biopsy. A diagnosis of AIH was based on the revised scoring system proposed by the International Autoimmune Hepatitis
1590-8658/$36.00 © 2009 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.dld.2009.04.009
52
Y. Miyake et al. / Digestive and Liver Disease 42 (2010) 51–54
Group [9]. A definite diagnosis of AIH based on this revised scoring system required a pretreatment score exceeding 15, while a probable diagnosis required a score between 10 and 15. Patients with an overlapping syndrome or a coexistent disease (for example, primary biliary cirrhosis, primary sclerosing cholangitis, nonalcoholic fatty liver disease, and alcohol-induced liver injury) were excluded from this analysis. Of the 176 patients, 136 were diagnosed as definite AIH, and the other 40 were diagnosed as probable AIH. Forty-two patients (26%) had concurrent autoimmune diseases: 18 had autoimmune thyroiditis; fours had Sjögren’s syndrome; three each had systemic lupus erythematosus, Graves’ disease, and ulcerative colitis; two each had autoimmune hemolytic anaemia, idiopathic thrombocytopenic purpura, progressive systemic sclerosis, and rheumatoid arthritis; one each had both autoimmune thyroiditis and autoimmune hemolytic anaemia, both systemic lupus erythematosus and Sjögren’s syndrome, and both autoimmune thyroiditis and Sjögren’s syndrome. Patients were diagnosed with acute presentation if they had acute onset of symptoms (for example, jaundice and/or fatigue and/or anorexia) in conjunction with serum bilirubin levels ≥5 mg/dL and/or serum alanine aminotransferase (ALT) levels ≥10fold the upper normal limit without any history of prior liver disease. Fifty-three patients (30%) showed acute presentation. The remaining patients, those with liver function abnormalities upon medical checkup or in their history, or patients without the criteria for acute presentation, were diagnosed as having the classical presentation. The titers of antinuclear antibodies (ANA) were measured using a standard IIF technique with HEp-2 cells. Smooth muscle antibodies (SMA) were assayed by the IIF technique using rat kidney and stomach cells. A serum titer of 1:40 or greater was positive for ANA or SMA. Antibodies to liver/kidney microsome type 1 (antiLKM-1) were measured using an enzyme-linked immunosorbent assay using recombinant cytochrome P4502D6 as the antigen, and a serum value of 50.0 index or greater was positive. Liver biopsy was performed with a Vim–Silverman needle (14G) under laparoscopy, or with a 17-G needle under ultrasonographic guidance, before or just after commencing the treatment. Liver biopsy specimens were evaluated by two pathologists and diagnosed as having either acute or chronic hepatitis. A diagnosis of acute hepatitis was based on the presence of histologically predominant zone 3 necrosis with minimal lymphoplasmacytic cell infiltration into portal tracts, in the absence of interface hepatitis or portal fibrosis. Liver biopsy specimens diagnosed as chronic hepatitis underwent histological staging based on the classification of Desmet et al. [10]. Histologically, acute hepatitis was shown in 10 patients. Initial treatment was defined as any therapy that was started within 3 months after the diagnosis of AIH. The treatment was continued until the normalization of serum ALT levels. To compare the clinicopathological characteristics between patients with acute presentation and those with classical presentation, we analyzed patient age, gender, pretreatment score based on the revised scoring system, concurrent autoimmune disease, laboratory data {albumin, bilirubin, aspartate aminotransferase (AST), alanine aminotransferase (ALT), immunoglobulin G (IgG), ANA, SMA, HLA DR4}, and histological features (staging of fibrosis, rosetting of liver cells, zone 3 necrosis). Furthermore, in 53 patients with acute presentation, we compared those with histological acute hepatitis to those with histological chronic hepatitis. 2.1. Statistics Statistical analysis was performed using the SPSS statistical program (release 11.0.1 J, SPSS, Inc., Chicago, IL).
Continuous variables were expressed as medians and ranges. The Mann–Whitney U-test was used to evaluate differences in the continuous variables. Dichotomous variables were compared by the 2 -test. Cumulative incidental rates were estimated using the log-rank test. P-values of less than 0.05 were considered significant. 3. Results 3.1. Clinical and laboratory findings Patients with acute presentation were indistinguishable from those with classical presentation by age and gender. In contrast, patients with acute presentation showed lower pretreatment scores and a lower frequency of definite diagnosis according to the revised scoring system proposed by the International Autoimmune Hepatitis Group [9]. Autoimmune thyroiditis was less frequently in patients with acute presentation (Table 1). On the other hand, of the 53 patients with acute presentation, the 10 with histological acute hepatitis were younger than the remaining 43 with chronic hepatitis (Table 2). Serum IgG levels were similar between patients with acute presentation and those with classical presentation (Table 1). In patients with acute presentation, those with acute hepatitis and those with chronic hepatitis were indistinguishable by serum levels of bilirubin, transaminase, and IgG (Table 2).
Table 1 Clinical features of AIH patients with acute presentation compared with those with classical presentation.
Patients (n) Age (years) Gender, female (%)
Acute presentation
Classical presentation
53 54 (16–76) 46 (87)
123 56 (18–79) 107 (87)
Criteria of the International Autoimmune Hepatitis Group Pretreatment score 17 (10–23) 18 (10–21) Definite diagnosis (%) 34 (64) 102 (83) Concurrent autoimmune disease, n (%) Autoimmune thyroiditis, n (%) Laboratory data Albumin (g/dL) Bilirubin (mg/dL) Bilirubin > 3.0 mg/dL, n (%) AST (IU/L)
P-value
0.51 0.97 0.01 0.006
8 (15)
34 (28)
0.07
2 (4)
18 (15)
0.04
3.6 (2.3–4.7) 5.0 (0.6–29.2) 38 (72) 753 (197–2330)
<0.0001 <0.0001 <0.0001 <0.0001
<0.0001
ALT (IU/L)
939 (109–2161)
IgG (mg/dL)
2430 (724–528)
IgG < 2000 mg/dL, n (%) ANA or ASMA ≥ 1:40, n (%) HLA DR4, n (%)
16 (30) 47 (89) 21/32 (66)
3.9 (2.1–5.1) 0.8 (0.3–5.0) 5 (4) 109 (28–769) 129 (23–1027) 2568 (1085–562) 23 (19) 120 (98) 39/55 (71)
Fibrosis staging, n (%) Acute hepatitis Chronic hepatitis F1 F2 F3 F4 F3 + F4
10 (19)
0 (0)
12 (23) 18 (34) 9 (17) 4 (7) 13 (24)
39 (32) 35 (28) 35 (28) 14 (12) 49 (40)
Rosetting of liver cells, n (%) Zone 3 necrosis, n (%)
19 (36) 28 (53)
30 (24) 24 (20)
<0.0001 0.20 0.09 0.01 0.61
0.05 0.12 <0.0001
Abbreviations: AST, aspartate aminotransferase; ALT, alanine aminotransferase; ALP, alkaline phosphatase; ULN, upper limit of normal; IgG, immunoglobulin G; ANA, antinuclear antibody; ASMA, anti-smooth muscle antibody; HLA, human leukocyte antigen.
Y. Miyake et al. / Digestive and Liver Disease 42 (2010) 51–54 Table 2 Clinical features of the 53 patients with acute presentation: comparison between the 10 patients with acute hepatitis and the 43 with chronic hepatitis.
Patients, n Age (years) Gender, female (%)
Acute hepatitis
Chronic hepatitis
P-value
10 37 (16–66) 8 (80)
43 58 (19–76) 38 (88)
0.006 0.48
Criteria of the International Autoimmune Hepatitis Group Pretreatment score 16 (10–20) 17 (10–23) Definite diagnosis (%) 5 (50) 29 (67) Concurrent autoimmune disease, n (%) Autoimmune thyroiditis, n (%)
0.37 0.30
2 (20)
6 (14)
0.63
0 (0)
2 (5)
0.49
Laboratory data Albumin (g/dL) Bilirubin (mg/dL) Bilirubin > 3.0 mg/dL, n (%) AST (IU/L) ALT (IU/L) IgG (mg/dL) IgG < 2000 mg/dL, n (%) ANA or ASMA ≥ 1:40, n (%) HLA DR4, n (%)
3.5 (3.0–4.7) 7.4 (1.8–29.2) 9 (90) 832 (197–2330) 1100 (335–2161) 2630 (1370–3602) 4 (40) 8 (80) 6/8 (75)
3.6 (2.3–4.4) 5.0 (0.6–25.8) 29 (67) 722 (230–1716) 930 (109–2132) 2394 (724–4528) 12 (30) 39 (91) 15/24 (63)
0.96 0.24 0.15 0.33 0.29 0.73 0.45 0.34 0.52
Rosetting of liver cells, n (%) Zone 3 necrosis, n (%)
5 (50) 10 (100)
14 (33) 18 (42)
0.30 0.0009
Abbreviations: AST, aspartate aminotransferase; ALT, alanine aminotransferase; ALP, alkaline phosphatase; ULN, upper limit of normal; IgG, immunoglobulin G; ANA, antinuclear antibody; ASMA, anti-smooth muscle antibody; HLA, human leukocyte antigen.
3.2. Immunoserologic features The ANA-positive frequency was similar between patients with acute presentation and those with classical presentation (79% vs. 89%; P = 0.07). The SMA-positive frequency was also similar between the groups (58% vs. 65%; P = 0.42). None had anti-LKM-1. However, patients with acute presentation less frequently had ANA of high titers (1:160 or greater) than those with classical presentation (49% vs. 72%; P = 0.005). On the other hand, in patients with acute presentation, the SMA-positive frequency and the frequency of ANA of high titers were similar between patients with acute hepatitis and those with chronic hepatitis (44% vs. 72%; P = 0.12 and 30% vs. 53%; P = 0.18). 3.3. HLA DR status Patients with acute presentation and those with classical presentation had similar frequencies of HLA DR4 (Table 1). None had DR3. In patients with acute presentation, the frequency of DR4 was similar between those with acute hepatitis and those with chronic hepatitis. 3.4. Histological features Histological acute hepatitis was more frequent in patients with acute presentation. None of those with classical presentation showed acute hepatitis. In contrast, advanced staging of fibrosis (F3 + F4) was less frequent in patients with acute presentation (Table 1). The frequency of liver cell rosetting was similar in both groups. However, patients with acute presentation showed zone 3 necrosis more frequently (Table 1). Furthermore, in patients with acute presentation, those with acute hepatitis showed zone 3 necrosis more frequently than those with chronic hepatitis (Table 2).
53
3.5. Response to corticosteroid treatment As an initial medical treatment, 135 of the 176 patients were treated with prednisolone (PSL) (≥20 mg/day). Of the 135 patients treated with PSL ≥20 mg/day, 15 were transferred to other hospitals without follow-up. Of the remaining 120 patients, 44 showed acute presentation. Patients with acute presentation were treated with higher doses of initial PSL than those with classical presentation {40 (20–60 mg/day) vs. 30 (20–45 mg/day); P < 0.0001}. In contrast, after 4-week PSL treatment, patients with acute presentation had a lower cumulative incidental rate of serum ALT normalization (41% vs. 62%; P = 0.01). The cumulative incidental rates of serum ALT normalization within 6 months after the introduction of PSL treatment were also similar in both groups (91% vs. 88%; P = 0.33). On the other hand, in patients with acute presentation, the cumulative incidental rates of serum ALT normalization after 4-week PSL treatment and those within 6 months after the introduction of PSL treatment were similar between patients with acute hepatitis and those with chronic hepatitis (44% vs. 44%; P = 0.79 and 100% vs. 89%; P = 0.19). 4. Discussion In this study, Japanese AIH patients with acute presentation showed histological zone 3 necrosis more frequently than those with classical presentation. This is consistent with the previous reports [4,5]. Furthermore, of patients with acute presentation, all 10 with histological acute hepatitis showed zone 3 necrosis, and the remaining patients with histological chronic hepatitis more frequently showed zone 3 necrosis than those with classical presentation (42% vs. 20%; P = 0.004). Thus, zone 3 necrosis is considered a histological characteristic of AIH with acute presentation. On the other hand, all 10 patients with histological acute hepatitis showed acute presentation. In contrast, 24% of patients with acute presentation had advanced staging of fibrosis, although this frequency is lower than that in patients with classical presentation. AIH with acute presentation is considered to include not only histological acute hepatitis but also acute exacerbation of the pre-existing chronic disease. Hypergammaglobulinemia and the positivity of autoantibodies are essential for a diagnosis of AIH. In Caucasian patients, these two factors are similar between patients with acute presentation and those with classical presentation [3,5]. In contrast, in the present study, patients with acute presentation showed a significantly lower frequency of the positivity for ANA or SMA and a slightly higher frequency of serum IgG levels < 2000 mg/dL. Thus, the frequency of a definite diagnosis according to the revised scoring system proposed by the International Autoimmune Hepatitis Group [9] was significantly lower in patients with acute presentation. Japanese patients with acute presentation may have atypical clinical features frequently, and these features may be different from those of Caucasian patients with acute presentation. In this study, concurrent extrahepatic autoimmune diseases occurred at similar rates between acute and classical presentation. In contrast, autoimmune thyroiditis occurred less frequently in patients with acute presentation. This result differs from the report by Kessler et al. [5]. Recently, a strong association between autoimmune thyroiditis and HLA DR4 was reported [11]. However, in this study, the frequency of HLA DR4 is similar between patients with acute presentation and those with classical presentation. Thus, factors other than HLA DR4 may contribute to the concurrence of autoimmune thyroiditis. In this study, of the 53 patients with acute presentation, the 10 with histological acute hepatitis were younger than the remaining patients with chronic hepatitis; however, these two groups were indistinguishable in the other clinical and laboratory findings. Furthermore, those with acute hepatitis were younger than those with
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Y. Miyake et al. / Digestive and Liver Disease 42 (2010) 51–54
classical presentation (P = 0.006). Previously, cases with acute presentation whose initial liver biopsy showed acute hepatitis were reported to show typical AIH by a repeat liver biopsy [12,13]. Some AIH patients are not referred at the time of the first flare-up because they are asymptomatic [14]. We speculate that AIH with acute hepatitis may reflect an early stage of the disease. On the other hand, of 176 patients in this study, the frequency of patients aged ≤40 years was higher in the 10 patients with histological acute presentation than in the 166 with chronic hepatitis (50% vs. 14%; P = 0.003). It is well recognized that although AIH activity is remitted during pregnancy, a flare-up often occurs after delivery [15]. Increased production of cortisol, progesterone, and oestrogen during pregnancy suppresses Th1 cytokine production (e.g., IL-12, interferon-␥) and enhances Th2 cytokine production (e.g., IL-4, IL-10) [16]. Hormonal factors may be associated with the pathogenesis of AIH with histological acute hepatitis. In conclusion, the present results agree with those of previous reports, in that zone 3 necrosis is a histological characteristic of AIH with acute presentation. AIH with acute presentation includes not only histological acute hepatitis but also acute exacerbation of pre-existing chronic disease. On the other hand, Japanese patients with acute presentation may have atypical clinical features frequently, and these features may be different from those of Caucasian patients with acute presentation. Further studies are required in order to confirm these findings. Conflict of interest statement None declared. References [1] Krawitt EL. Autoimmune hepatitis. N Engl J Med 2006;354:54–66.
[2] Miyake Y, Yamamoto K. Current status of autoimmune hepatitis in Japan. Acta Med Okayama 2008;62:217–26. [3] Nikias GA, Batts KP, Czaja AJ. The nature and prognostic implications of autoimmune hepatitis with an acute presentation. J Hepatol 1994;21:866–71. [4] Hofer H, Oesterreicher C, Wrba F, Ferenci P, Penner E. Centrilobular necrosis in autoimmune hepatitis: a histological feature associated with acute clinical presentation. J Clin Pathol 2006;59:246–9. [5] Kessler WR, Cummings OW, Eckert G, Chalasani N, Lumeng L, Kwo PY. Fulminant hepatic failure as the initial presentation of acute autoimmune hepatitis. Clin Gastroenterol Hepatol 2004;2:625–31. [6] Donaldson PT, Doherty DG, Hayllar KM, McFarlane IG, Johnson PJ, Williams R. Susceptibility to autoimmune chronic active hepatitis: human leukocyte antigens DR4 and A1-B8-DR3 are independent risk factors. Hepatology 1991;13:701–70. [7] Toda G, Zeniya M, Watanabe F, Imawari M, Kiyosawa K, Nishioka M, et al. Present status of autoimmune hepatitis in Japan—correlating the characteristics with international criteria in an area with a high rate of HCV infection. Japanese National Study Group of Autoimmune Hepatitis. J Hepatol 1997;26:1207–12. [8] Czaja AJ, Carpenter HA, Santrach PJ, Moore SB. Significance of HLA DR4 in type 1 autoimmune hepatitis. Gastroenterology 1993;105:1502–7. [9] Alvarez F, Berg PA, Bianchi FB, Bianchi L, Burroughs AK, Cancado EL, et al. International Autoimmune Hepatitis Group report: review of criteria for diagnosis of autoimmune hepatitis. J Hepatol 1999;31:929–38. [10] Desmet VJ, Gerber M, Hoofnagle JH, Manns M, Scheuer PJ. Classification of chronic hepatitis: diagnosis, grading and staging. Hepatology 1994;19:1513–20. [11] Zeitlin AA, Heward JM, Newby PR, Carr-Smith JD, Franklyn JA, Gough SC, et al. Analysis of HLA class II genes in Hashimoto’s thyroiditis reveals differences compared to Graves’ disease. Genes Immun 2008;9:358–63. [12] Singh R, Nair S, Farr G, Mason A, Perrillo R. Acute autoimmune hepatitis presenting with centrizonal liver disease: case report and review of the literature. Am J Gastroenterol 2002;97:2670–3. [13] Pratt DS, Fawaz KA, Rabson A, Dellelis R, Kaplan MM. A novel histological lesion in glucocorticoid-responsive chronic hepatitis. Gastroenterology 1997;113:664–8. [14] Dufour JF, Zimmermann M, Reichen J. Severe autoimmune hepatitis in patients with previous spontaneous recovery of a flare. J Hepatol 2002;37:748–52. [15] Buchel E, Van Steenbergen W, Nevens F, Fevery J. Improvement of autoimmune hepatitis during pregnancy followed by flare-up after delivery. Am J Gastroenterol 2002;97:3160–5. [16] Wilder RL. Hormones, pregnancy, and autoimmune diseases. Ann N Y Acad Sci 1998;840:45–50.
Contents lists available at ScienceDirect
Digestive and Liver Disease journal homepage: www.elsevier.com/locate/dld
Liver, Pancreas and Biliary Tract
Autoimmune hepatitis with acute presentation in Japan Y. Miyake a,b,∗ , Y. Iwasaki b , H. Kobashi b , T. Yasunaka b , F. Ikeda a,b , A. Takaki b , K. Yamamoto a,b a b
Department of Molecular Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan Department of Gastroenterology & Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
a r t i c l e
i n f o
Article history: Received 21 November 2008 Accepted 15 April 2009 Available online 26 May 2009 Keywords: Acute exacerbation Acute hepatitis Cirrhosis Zone 3 necrosis
a b s t r a c t Background: In Caucasians with autoimmune hepatitis, patients with acute presentation have autoimmune thyroiditis and histological zone 3 necrosis more frequently. Aim: We aimed at investigating clinical features of Japanese autoimmune hepatitis patients with acute presentation. Methods: Of 176 patients retrospectively reviewed, 53 were diagnosed with acute presentation. Results: Patients with acute presentation had higher serum levels of bilirubin and transaminase, lower frequencies of autoimmune thyroiditis and antinuclear antibodies of 1:160 or greater, and a higher frequency of zone 3 necrosis. Of the 53 patients with acute presentation, 10 showed histological acute hepatitis; however, advanced staging of fibrosis was found in 13 patients. In patients with acute presentation, those with histological acute hepatitis were younger than those with chronic hepatitis. The cumulative incidental rate of the normalization of serum alanine aminotransferase levels with prednisolone treatment was similar between patients with acute presentation and those with classical presentation. Conclusions: In line with previous results, zone 3 necrosis is a histological characteristic of autoimmune hepatitis with acute presentation. Autoimmune hepatitis with acute presentation includes not only histological acute hepatitis but also acute exacerbation of pre-existing chronic disease. On the other hand, Japanese patients with acute presentation may also have different clinical features from Caucasian patients. © 2009 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.
1. Introduction Autoimmune hepatitis (AIH), defined as a chronic hepatitis of unknown aetiology, is characterized by circulating autoantibodies, hypergammaglobulinemia, and the presence of interface hepatitis and lymphoplasmacytic infiltration on histological examination [1,2]. The prognosis is generally good with immunosuppressive treatment. Recently, the number of patients with acute presentation has increased. Czaja and co-workers [3] reported that acute and classical presentation of AIH were indistinguishable from each other by clinical and laboratory features. In contrast, Hofer et al. [4] reported that zone 3 necrosis was a histological characteristic of AIH with acute presentation. Kessler et al. [5] reported that patients with acute presentation had severe hepatitis and autoimmune thyroiditis more frequently than those with classical presentation. The clinical features of AIH with acute presentation have not been fully elucidated.
∗ Corresponding author at: Department of Molecular Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1, Shikata-cho, Okayama 700-8558, Japan. Tel.: +81 86 235 7219; fax: +81 86 225 5991. E-mail address: [email protected] (Y. Miyake).
On the other hand, the clinical features of Japanese AIH patients are different from those of Caucasian patients [2]. These are attributed to differences in human leukocyte antigen (HLA) DR status. In Caucasian patients, HLA DR3 and DR4 are independently susceptible to AIH [6], while DR4 is predominant in Japanese patients; there are few Japanese patients with DR3 [7]. Patients with DR3 are younger and have a higher frequency of treatment failure; however, those with DR4 frequently have concurrent extrahepatic autoimmune disease and respond better to corticosteroid treatment [8]. The clinical features of AIH with acute presentation may differ between Japanese and Caucasian patients. In the present study, we assessed the clinical features of Japanese AIH patients with acute presentation. 2. Patients and methods One-hundred-and-seventy-six patients with type 1 AIH (153 females, 23 males, median age 55 years) were admitted to the Okayama University Hospital or six affiliated hospitals between March 1989 and April 2008. All patients were seronegative for hepatitis B surface antigen, anti-hepatitis C virus antibody, hepatitis C virus RNA, and anti-mitochondrial antibody, and all underwent liver biopsy. A diagnosis of AIH was based on the revised scoring system proposed by the International Autoimmune Hepatitis
1590-8658/$36.00 © 2009 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.dld.2009.04.009
52
Y. Miyake et al. / Digestive and Liver Disease 42 (2010) 51–54
Group [9]. A definite diagnosis of AIH based on this revised scoring system required a pretreatment score exceeding 15, while a probable diagnosis required a score between 10 and 15. Patients with an overlapping syndrome or a coexistent disease (for example, primary biliary cirrhosis, primary sclerosing cholangitis, nonalcoholic fatty liver disease, and alcohol-induced liver injury) were excluded from this analysis. Of the 176 patients, 136 were diagnosed as definite AIH, and the other 40 were diagnosed as probable AIH. Forty-two patients (26%) had concurrent autoimmune diseases: 18 had autoimmune thyroiditis; fours had Sjögren’s syndrome; three each had systemic lupus erythematosus, Graves’ disease, and ulcerative colitis; two each had autoimmune hemolytic anaemia, idiopathic thrombocytopenic purpura, progressive systemic sclerosis, and rheumatoid arthritis; one each had both autoimmune thyroiditis and autoimmune hemolytic anaemia, both systemic lupus erythematosus and Sjögren’s syndrome, and both autoimmune thyroiditis and Sjögren’s syndrome. Patients were diagnosed with acute presentation if they had acute onset of symptoms (for example, jaundice and/or fatigue and/or anorexia) in conjunction with serum bilirubin levels ≥5 mg/dL and/or serum alanine aminotransferase (ALT) levels ≥10fold the upper normal limit without any history of prior liver disease. Fifty-three patients (30%) showed acute presentation. The remaining patients, those with liver function abnormalities upon medical checkup or in their history, or patients without the criteria for acute presentation, were diagnosed as having the classical presentation. The titers of antinuclear antibodies (ANA) were measured using a standard IIF technique with HEp-2 cells. Smooth muscle antibodies (SMA) were assayed by the IIF technique using rat kidney and stomach cells. A serum titer of 1:40 or greater was positive for ANA or SMA. Antibodies to liver/kidney microsome type 1 (antiLKM-1) were measured using an enzyme-linked immunosorbent assay using recombinant cytochrome P4502D6 as the antigen, and a serum value of 50.0 index or greater was positive. Liver biopsy was performed with a Vim–Silverman needle (14G) under laparoscopy, or with a 17-G needle under ultrasonographic guidance, before or just after commencing the treatment. Liver biopsy specimens were evaluated by two pathologists and diagnosed as having either acute or chronic hepatitis. A diagnosis of acute hepatitis was based on the presence of histologically predominant zone 3 necrosis with minimal lymphoplasmacytic cell infiltration into portal tracts, in the absence of interface hepatitis or portal fibrosis. Liver biopsy specimens diagnosed as chronic hepatitis underwent histological staging based on the classification of Desmet et al. [10]. Histologically, acute hepatitis was shown in 10 patients. Initial treatment was defined as any therapy that was started within 3 months after the diagnosis of AIH. The treatment was continued until the normalization of serum ALT levels. To compare the clinicopathological characteristics between patients with acute presentation and those with classical presentation, we analyzed patient age, gender, pretreatment score based on the revised scoring system, concurrent autoimmune disease, laboratory data {albumin, bilirubin, aspartate aminotransferase (AST), alanine aminotransferase (ALT), immunoglobulin G (IgG), ANA, SMA, HLA DR4}, and histological features (staging of fibrosis, rosetting of liver cells, zone 3 necrosis). Furthermore, in 53 patients with acute presentation, we compared those with histological acute hepatitis to those with histological chronic hepatitis. 2.1. Statistics Statistical analysis was performed using the SPSS statistical program (release 11.0.1 J, SPSS, Inc., Chicago, IL).
Continuous variables were expressed as medians and ranges. The Mann–Whitney U-test was used to evaluate differences in the continuous variables. Dichotomous variables were compared by the 2 -test. Cumulative incidental rates were estimated using the log-rank test. P-values of less than 0.05 were considered significant. 3. Results 3.1. Clinical and laboratory findings Patients with acute presentation were indistinguishable from those with classical presentation by age and gender. In contrast, patients with acute presentation showed lower pretreatment scores and a lower frequency of definite diagnosis according to the revised scoring system proposed by the International Autoimmune Hepatitis Group [9]. Autoimmune thyroiditis was less frequently in patients with acute presentation (Table 1). On the other hand, of the 53 patients with acute presentation, the 10 with histological acute hepatitis were younger than the remaining 43 with chronic hepatitis (Table 2). Serum IgG levels were similar between patients with acute presentation and those with classical presentation (Table 1). In patients with acute presentation, those with acute hepatitis and those with chronic hepatitis were indistinguishable by serum levels of bilirubin, transaminase, and IgG (Table 2).
Table 1 Clinical features of AIH patients with acute presentation compared with those with classical presentation.
Patients (n) Age (years) Gender, female (%)
Acute presentation
Classical presentation
53 54 (16–76) 46 (87)
123 56 (18–79) 107 (87)
Criteria of the International Autoimmune Hepatitis Group Pretreatment score 17 (10–23) 18 (10–21) Definite diagnosis (%) 34 (64) 102 (83) Concurrent autoimmune disease, n (%) Autoimmune thyroiditis, n (%) Laboratory data Albumin (g/dL) Bilirubin (mg/dL) Bilirubin > 3.0 mg/dL, n (%) AST (IU/L)
P-value
0.51 0.97 0.01 0.006
8 (15)
34 (28)
0.07
2 (4)
18 (15)
0.04
3.6 (2.3–4.7) 5.0 (0.6–29.2) 38 (72) 753 (197–2330)
<0.0001 <0.0001 <0.0001 <0.0001
<0.0001
ALT (IU/L)
939 (109–2161)
IgG (mg/dL)
2430 (724–528)
IgG < 2000 mg/dL, n (%) ANA or ASMA ≥ 1:40, n (%) HLA DR4, n (%)
16 (30) 47 (89) 21/32 (66)
3.9 (2.1–5.1) 0.8 (0.3–5.0) 5 (4) 109 (28–769) 129 (23–1027) 2568 (1085–562) 23 (19) 120 (98) 39/55 (71)
Fibrosis staging, n (%) Acute hepatitis Chronic hepatitis F1 F2 F3 F4 F3 + F4
10 (19)
0 (0)
12 (23) 18 (34) 9 (17) 4 (7) 13 (24)
39 (32) 35 (28) 35 (28) 14 (12) 49 (40)
Rosetting of liver cells, n (%) Zone 3 necrosis, n (%)
19 (36) 28 (53)
30 (24) 24 (20)
<0.0001 0.20 0.09 0.01 0.61
0.05 0.12 <0.0001
Abbreviations: AST, aspartate aminotransferase; ALT, alanine aminotransferase; ALP, alkaline phosphatase; ULN, upper limit of normal; IgG, immunoglobulin G; ANA, antinuclear antibody; ASMA, anti-smooth muscle antibody; HLA, human leukocyte antigen.
Y. Miyake et al. / Digestive and Liver Disease 42 (2010) 51–54 Table 2 Clinical features of the 53 patients with acute presentation: comparison between the 10 patients with acute hepatitis and the 43 with chronic hepatitis.
Patients, n Age (years) Gender, female (%)
Acute hepatitis
Chronic hepatitis
P-value
10 37 (16–66) 8 (80)
43 58 (19–76) 38 (88)
0.006 0.48
Criteria of the International Autoimmune Hepatitis Group Pretreatment score 16 (10–20) 17 (10–23) Definite diagnosis (%) 5 (50) 29 (67) Concurrent autoimmune disease, n (%) Autoimmune thyroiditis, n (%)
0.37 0.30
2 (20)
6 (14)
0.63
0 (0)
2 (5)
0.49
Laboratory data Albumin (g/dL) Bilirubin (mg/dL) Bilirubin > 3.0 mg/dL, n (%) AST (IU/L) ALT (IU/L) IgG (mg/dL) IgG < 2000 mg/dL, n (%) ANA or ASMA ≥ 1:40, n (%) HLA DR4, n (%)
3.5 (3.0–4.7) 7.4 (1.8–29.2) 9 (90) 832 (197–2330) 1100 (335–2161) 2630 (1370–3602) 4 (40) 8 (80) 6/8 (75)
3.6 (2.3–4.4) 5.0 (0.6–25.8) 29 (67) 722 (230–1716) 930 (109–2132) 2394 (724–4528) 12 (30) 39 (91) 15/24 (63)
0.96 0.24 0.15 0.33 0.29 0.73 0.45 0.34 0.52
Rosetting of liver cells, n (%) Zone 3 necrosis, n (%)
5 (50) 10 (100)
14 (33) 18 (42)
0.30 0.0009
Abbreviations: AST, aspartate aminotransferase; ALT, alanine aminotransferase; ALP, alkaline phosphatase; ULN, upper limit of normal; IgG, immunoglobulin G; ANA, antinuclear antibody; ASMA, anti-smooth muscle antibody; HLA, human leukocyte antigen.
3.2. Immunoserologic features The ANA-positive frequency was similar between patients with acute presentation and those with classical presentation (79% vs. 89%; P = 0.07). The SMA-positive frequency was also similar between the groups (58% vs. 65%; P = 0.42). None had anti-LKM-1. However, patients with acute presentation less frequently had ANA of high titers (1:160 or greater) than those with classical presentation (49% vs. 72%; P = 0.005). On the other hand, in patients with acute presentation, the SMA-positive frequency and the frequency of ANA of high titers were similar between patients with acute hepatitis and those with chronic hepatitis (44% vs. 72%; P = 0.12 and 30% vs. 53%; P = 0.18). 3.3. HLA DR status Patients with acute presentation and those with classical presentation had similar frequencies of HLA DR4 (Table 1). None had DR3. In patients with acute presentation, the frequency of DR4 was similar between those with acute hepatitis and those with chronic hepatitis. 3.4. Histological features Histological acute hepatitis was more frequent in patients with acute presentation. None of those with classical presentation showed acute hepatitis. In contrast, advanced staging of fibrosis (F3 + F4) was less frequent in patients with acute presentation (Table 1). The frequency of liver cell rosetting was similar in both groups. However, patients with acute presentation showed zone 3 necrosis more frequently (Table 1). Furthermore, in patients with acute presentation, those with acute hepatitis showed zone 3 necrosis more frequently than those with chronic hepatitis (Table 2).
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3.5. Response to corticosteroid treatment As an initial medical treatment, 135 of the 176 patients were treated with prednisolone (PSL) (≥20 mg/day). Of the 135 patients treated with PSL ≥20 mg/day, 15 were transferred to other hospitals without follow-up. Of the remaining 120 patients, 44 showed acute presentation. Patients with acute presentation were treated with higher doses of initial PSL than those with classical presentation {40 (20–60 mg/day) vs. 30 (20–45 mg/day); P < 0.0001}. In contrast, after 4-week PSL treatment, patients with acute presentation had a lower cumulative incidental rate of serum ALT normalization (41% vs. 62%; P = 0.01). The cumulative incidental rates of serum ALT normalization within 6 months after the introduction of PSL treatment were also similar in both groups (91% vs. 88%; P = 0.33). On the other hand, in patients with acute presentation, the cumulative incidental rates of serum ALT normalization after 4-week PSL treatment and those within 6 months after the introduction of PSL treatment were similar between patients with acute hepatitis and those with chronic hepatitis (44% vs. 44%; P = 0.79 and 100% vs. 89%; P = 0.19). 4. Discussion In this study, Japanese AIH patients with acute presentation showed histological zone 3 necrosis more frequently than those with classical presentation. This is consistent with the previous reports [4,5]. Furthermore, of patients with acute presentation, all 10 with histological acute hepatitis showed zone 3 necrosis, and the remaining patients with histological chronic hepatitis more frequently showed zone 3 necrosis than those with classical presentation (42% vs. 20%; P = 0.004). Thus, zone 3 necrosis is considered a histological characteristic of AIH with acute presentation. On the other hand, all 10 patients with histological acute hepatitis showed acute presentation. In contrast, 24% of patients with acute presentation had advanced staging of fibrosis, although this frequency is lower than that in patients with classical presentation. AIH with acute presentation is considered to include not only histological acute hepatitis but also acute exacerbation of the pre-existing chronic disease. Hypergammaglobulinemia and the positivity of autoantibodies are essential for a diagnosis of AIH. In Caucasian patients, these two factors are similar between patients with acute presentation and those with classical presentation [3,5]. In contrast, in the present study, patients with acute presentation showed a significantly lower frequency of the positivity for ANA or SMA and a slightly higher frequency of serum IgG levels < 2000 mg/dL. Thus, the frequency of a definite diagnosis according to the revised scoring system proposed by the International Autoimmune Hepatitis Group [9] was significantly lower in patients with acute presentation. Japanese patients with acute presentation may have atypical clinical features frequently, and these features may be different from those of Caucasian patients with acute presentation. In this study, concurrent extrahepatic autoimmune diseases occurred at similar rates between acute and classical presentation. In contrast, autoimmune thyroiditis occurred less frequently in patients with acute presentation. This result differs from the report by Kessler et al. [5]. Recently, a strong association between autoimmune thyroiditis and HLA DR4 was reported [11]. However, in this study, the frequency of HLA DR4 is similar between patients with acute presentation and those with classical presentation. Thus, factors other than HLA DR4 may contribute to the concurrence of autoimmune thyroiditis. In this study, of the 53 patients with acute presentation, the 10 with histological acute hepatitis were younger than the remaining patients with chronic hepatitis; however, these two groups were indistinguishable in the other clinical and laboratory findings. Furthermore, those with acute hepatitis were younger than those with
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Y. Miyake et al. / Digestive and Liver Disease 42 (2010) 51–54
classical presentation (P = 0.006). Previously, cases with acute presentation whose initial liver biopsy showed acute hepatitis were reported to show typical AIH by a repeat liver biopsy [12,13]. Some AIH patients are not referred at the time of the first flare-up because they are asymptomatic [14]. We speculate that AIH with acute hepatitis may reflect an early stage of the disease. On the other hand, of 176 patients in this study, the frequency of patients aged ≤40 years was higher in the 10 patients with histological acute presentation than in the 166 with chronic hepatitis (50% vs. 14%; P = 0.003). It is well recognized that although AIH activity is remitted during pregnancy, a flare-up often occurs after delivery [15]. Increased production of cortisol, progesterone, and oestrogen during pregnancy suppresses Th1 cytokine production (e.g., IL-12, interferon-␥) and enhances Th2 cytokine production (e.g., IL-4, IL-10) [16]. Hormonal factors may be associated with the pathogenesis of AIH with histological acute hepatitis. In conclusion, the present results agree with those of previous reports, in that zone 3 necrosis is a histological characteristic of AIH with acute presentation. AIH with acute presentation includes not only histological acute hepatitis but also acute exacerbation of pre-existing chronic disease. On the other hand, Japanese patients with acute presentation may have atypical clinical features frequently, and these features may be different from those of Caucasian patients with acute presentation. Further studies are required in order to confirm these findings. Conflict of interest statement None declared. References [1] Krawitt EL. Autoimmune hepatitis. N Engl J Med 2006;354:54–66.
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